Embryonic development of the pancreas involves an epithelial endoderm budding from the primitive gut tube into surrounding mesenchyme (splanchnic mesoderm). The process is described in detail in the publication by R. Pictet and W. Rutter, HANDBOOK OF PHYSIOLOGY, Vol. 1, Section 7, Endocrinology: Endocrine Pancreas, D. Steiner and N. Freinkel, eds., Amer. Physiol. Soc. L972, pp. 25-66. The sequential epithelial/mesenchymal interactions results in the formation of both exocrine and endocrine pancreas. Later in adult life, it is believed that very little endocrine neogenesis occurs in the pancreas. This has led to the conclusion of some investigators in the diabetes field to consider the beta cell (the beta cell is the source cell for insulin) a "terminal" cell. A terminal cell is a fully differentiated cell that exhibits very little mitosis in adult life, and consequently, at birth, an individual has the full complement of these cells. The terminal nature of the beta cell has far reaching implications in the field of diabetes since beta cell destruction or functional impairment results in a devastating clinical situation without any hope of new, healthy, beta cell formation occurring to alleviate the disease.
In the past, many investigators have studied the effects of various conditions on the mitotic activity of pre-existing beta cells in the pancreas. These conditions have included the effect of diet, hormones, partial pancreatectomy, diabetogenic chemicals, genetic manipulation, sulfonylureas, insulin antibody, glucose, and amino acids. See, for example, J. Logothetopoulos, HANDBOOK OF PHYSIOLOGY, Vol. 1, Section 7, Endocrinology: Endocrine Pancreas, D. Steiner and N. Freinkel, eds., Amer. Physiol. Soc. 1972, pp. 67-76. The crux of these studies has been to increase the mitotic activity of pre-existing beta cells. None of these studies has dealt with the concept of the neoformation or regeneration of islet beta cells from non-islet entities (islets are groups of beta cells).
Many investigators have found that in vitro culture of fetal pancreas exhibits a high rate of beta cell mitosis and also some evidence of neoformation of beta cells from "budding islets" which seems to result from true neogenetic process (morphogenesis and histogenesis); et al., Morphological Study of Cultured Pancreatic Fetal Islets: Diabetes, Vol. 29, Jan. 1980, pp. 16-21. In addition, Archer and Jai (U.S. Pat. No. 4,439,521; Mar. 27, 1984; Method for Producing Self-Reproducing Mammalian Pancreatic Islet-like Structures) describe a method for producing pancreatic islet-like structures using in vitro culturing techniques. They have been able to increase islet tissue using standard tissue culture technology of pancreatic islets, pancreatic duct pieces, cell clusters of pancreas, cell tissues obtained as by products of the culturing method, or previously produced islet-like structures.
The invention of this application relates to a method and composition for regenerating cells in a post natal subject, cells which do not normally regenerate apart from fetal development. Specifically, islet cells of the pancreas may be regenerated.